The present invention relates to a preparation capable of releasing a medicinal substance at a targeted site in the intestine, which can selectively deliver a medicinal substance to the large intestine and the like, and a method for preparation thereof.
Selective delivery of a medicinal substance to a specific site in the intestine has been desired in pharmacotherapy, for example, a local therapy for inflammatory disease in the gastrointestinal tract such as ulcerative colitis or Crohn""s disease, an oral administrative therapy with a medicinal substance of a peptide which is apt to be decomposed chemically or enzymatically in any site except for a specific site in the intestine such as the large intestine, or with a medicinal substance whose absorption site in intestine is limited, or the like.
In order to efficiently realize the selective delivery of a medicinal substance in the intestine, it is necessary to design a preparation considering the physical and physiological environment in the human gastrointestinal tract and the traveling time of the preparation through the gastrointestinal tract. With respect to the physical and physiological environment in the gastrointestinal tract, it is recognized that the value of pH in the stomach is usually 1.8 to 4.5 and the value of pH in the intestine is 6.5 to 7.5 in a healthy human. According to the results of the widespread research of Davis et al., in a human, the residence time of a preparation in the stomach is 0.5 to 10 hours and further not only the inter-individual variation thereof is large, but also the residence time is considerably influenced, for example, by a condition of feeding, a size of the preparation to be administered and the like, while the traveling time of a preparation through the small intestine is generally recognized to be 3xc2x11 hours and the variation is relatively small (Journal of Controlled Release, 2, 27-38 (1985)).
With respect to a preparation which can selectively deliver a medicinal substance to a specific site in the intestine, hitherto various researches have been done. There have been proposed a preparation wherein a sustained release preparation is coated with an enteric film (Theeuwes et al, Annals of the New York Academy of Science, 618, 428-440 (1991)), a preparation utilizing a technique for controlling the starting time of the release (Ishino et al, Chemical and Pharmaceutical Bulletin, 40, 3036-3041 (1992), Japanese Unexamined Patent Publication No. 72417/1991, Japanese Unexamined Patent Publication No. 256166/1994) and the like, as well as an enteric preparation and a sustained release preparation.
However, in case of using an enteric preparation, since the medicinal substance is released rapidly at the upper small intestine, almost of the medicinal substance is wasted by absorption or decomposition before the medicinal substance is delivered to the targeted site in the intestine. In case of using the sustained release preparation, since the medicinal substance is released gradually, a considerable amount of the medicinal substance is released during the stay of the preparation in the stomach and during the passing of the preparation through the intestine to the targeted site. Further, an attempt to suppress an endogastric releasing of a medicinal substance by coating a sustained release preparation with an enteric film has not completely solved a problem of releasing of a medicinal substance during the passing through the intestine to the targeted site.
Furthermore, recently there has been proposed a method for selectively releasing at the large intestine a medicinal active ingredient coated or matrixed with a polymer, which is specifically decomposed by enterobacteria, such as chitosan and azopolymers, (U.S. Pat. No. 5,217,720; Saffran, Science, 233, 1081-1084 (1986)). However, in this method, the decomposition rate of the polymer cannot be controlled and the delivery to any site other than the large intestine is principally impossible, though this method is preferable as to the selectivity of a release site. For practical use, there are still many problems as regarding the safety and the productivity of the polymer itself because the polymer has never been administered to humans.
Meanwhile, diltiazem hydrochloride granule coated with a mixed film of stearic acid and Eudragit RS is known as a preparation coated with a film containing a hydrophobic organic compound (Japanese Unexamined Patent Publication No. 120571/1998). A preparation coated with a mixed film of a hydrophobic organic compound and an enteric polymer is unknown. Further, the above-mentioned diltiazem hydrochloride granule is not with the intention of releasing a medicinal substance at a desired site in the intestine but a sustained release preparation for sustainably releasing a medicinal substance after dosage thereof.
The present invention aims to provide a highly practicable preparation for oral administration capable of selectively delivering a medicinal substance at any site in the intestine by not using an extraordinary material but using a safe raw material usually used for pharmaceutical preparation.
As the abovementioned problems, the inventors have found that a preparation in which a core material containing a medicinal substance coated with a mixed film of hydrophobic organic compound-enteric polymer, has a unique releasing behavior in that the preparation releases no medicinal substance in an acidic solution but releases a medicinal substance quickly in a neutral or basic solution after a certain period of time (lag-time). The inventors have also found that the lag-time can be controlled by changing the coating amount of film and the ratio of the amount of the hydrophobic organic compound to the amount of the enteric polymer.
According to a preparation of the present invention, a medicinal substance is not released in an acidic condition such as endogastric condition after dosage. The medicinal substance is not released at all during a certain period of time, even though the preparation is discharged from the stomach and the value of pH changes into a neutral or weakly acidic condition. The medicinal substance can be released when the preparation reaches the targeted site in the intestine after said certain period.
Namely, the invention is a preparation capable of releasing a medicinal substance at a targeted site in the intestine, wherein a core material containing a medicinal substance is coated with a mixed film of a hydrophobic organic compound and an enteric polymer or shellac.
The invention is further directed to such a preparation in which the hydrophobic organic compound is one or more of a higher fatty acid having 6 to 22 carbon atoms which may have an unsaturated bond, a higher alcohol having 6 to 22 carbon atoms which may have an unsaturated bond, a triglyceride of the higher fatty acid having 6 to 22 carbon atoms which may have an unsaturated bond, and a natural fat which may be hydrogenated; and in which the enteric polymer is one or more of an enteric cellulose derivative, an enteric acrylic copolymer, an enteric maleic copolymer, and an enteric polyvinyl derivative.
The invention is still further directed to such a preparation in which the higher fatty acid having 6 to 22 carbon atoms which may have an unsaturated bond is stearic acid, lauric acid, myristic acid, palmitic acid, or behenic acid; the higher alcohol having 6 to 22 carbon atoms which may have an unsaturated bond is lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, or behenyl alcohol; the triglyceride of the fatty acid having 6 to 22 carbon atoms which may have an unsaturated bond is glyceryl tristearate, glyceryl trimyristate, glyceryl tripalmitate, or glyceryl trilaurate; the natural fat which may be hydrogenated is hydrogenated castor oil, hydrogenated coconut oil, or beef tallow; the enteric cellulose derivative is hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, hydroxymethylethylcellulose phthalate, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate maleate, cellulose benzoate phthalate, cellulose propionate phthalate, methylcellulose phthalate, carboxymethylethylcellulose or ethylhydroxyethylcellulose phthalate; the enteric acrylic copolymer is styrene.acrylic acid copolymer, methyl acrylate.acrylic acid copolymer, methyl acrylate.methacrylic acid copolymer, butyl acrylate.styrene.acrylic acid copolymer, methacrylic acid.methyl methacrylate copolymer, methacrylic acid.ethyl acrylate copolymer, or methyl acrylate.methacrylic acid.octyl acrylate copolymer; the enteric maleic copolymer is vinylacetate.maleic acid anhydride copolymer, styrene.maleic acid anhydride copolymer, styrene.maleic acid monoester copolymer, vinylmethylether.maleic acid anhydride copolymer, ethylene.maleic acid anhydride copolymer, vinylbutylether.maleic acid anhydride copolymer, acrylonitrile.methyl acrylate.maleic acid anhydride copolymer, or butyl acrylate.styrene.maleic acid anhydride copolymer; and the enteric polyvinyl derivative is polyvinyl alcohol phthalate, polyvinylacetal phthalate, polyvinyl butylate phthalate, or polyvinylacetoacetal phthalate.
The invention still further relates to such a prepaaration in which the hidrophobic organic compound is steaaric acid and the enteric polymer is methacrilic acid.methyl methacrylate copolymer.
A further embodiment of the invention relates to such a preparation in which the mixing ratio of the amount of the hydrophobic organic compound to the amount of the enteric polymer in the mixed film of hydrophobic organic compoundxe2x80x94enteric polymer is within a range of 30:70 to 80:20.
A still further embodiment of the invention is such a preparation in which the coating ratio of the mixed film of hydrophobic organic compoundxe2x80x94enteric polymer is within a range of 20 to 100% by weight.
Yet a further embodiment of the invention is such a preparation in which the medicinal substance is not released during at least 10 hours in the first fluid of the disintegration test in Japanese Pharmacopoeia XIII and is not released during at least 2 hours in the second fluid of the disintegration test in Japanese Pharmacopoeia XIII.
Another embodiment of the invention is a method for preparing a pharmaceutical preparation capable of releasing a medicinal substance at a targeted site in the intestine, wherein a core material containing a medicinal substance is spray-coated with a coating solution in which a hydrophobic organic compound and an enteric poltner are dissolved in a same solvent.